NM_018129.4:c.552G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_018129.4(PNPO):c.552G>A(p.Leu184Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0738 in 1,610,284 control chromosomes in the GnomAD database, including 4,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 366 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4567 hom. )

Consequence

PNPO
NM_018129.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.967

Variant links:

Genes affected

PNPO (HGNC:30260): (pyridoxamine 5'-phosphate oxidase) The enzyme encoded by this gene catalyzes the terminal, rate-limiting step in the synthesis of pyridoxal 5'-phosphate, also known as vitamin B6. Vitamin B6 is a required co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. Mutations in this gene result in pyridoxamine 5'-phosphate oxidase (PNPO) deficiency, a form of neonatal epileptic encephalopathy. [provided by RefSeq, Oct 2008]

PNPO links:

ENSG00000263798 (HGNC:):

ENSG00000263798 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 17-47946328-G-A is Benign according to our data. Variant chr17-47946328-G-A is described in ClinVar as [Benign]. Clinvar id is 129983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-47946328-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.967 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPO	NM_018129.4 link	c.552G>A	p.Leu184Leu	synonymous_variant	Exon 6 of 7	ENST00000642017.2	NP_060599.1	Q9NVS9-1V9HW45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPO	ENST00000642017.2 link	c.552G>A	p.Leu184Leu	synonymous_variant	Exon 6 of 7		NM_018129.4	ENSP00000493302.2		Q9NVS9-1

Frequencies

GnomAD3 genomes

AF:

0.0636

AC:

9668

AN:

152080

Hom.:

365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0315

Gnomad AMI

AF:

0.0297

Gnomad AMR

AF:

0.0585

Gnomad ASJ

AF:

0.0985

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0886

Gnomad FIN

AF:

0.0915

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0812

Gnomad OTH

AF:

0.0728

GnomAD3 exomes

AF:

0.0685

AC:

17168

AN:

250688

Hom.:

738

AF XY:

0.0721

AC XY:

9775

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.0311

Gnomad AMR exome

AF:

0.0413

Gnomad ASJ exome

AF:

0.0935

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0947

Gnomad FIN exome

AF:

0.0864

Gnomad NFE exome

AF:

0.0803

Gnomad OTH exome

AF:

0.0733

GnomAD4 exome

AF:

0.0749

AC:

109163

AN:

1458086

Hom.:

4567

Cov.:

AF XY:

0.0764

AC XY:

55453

AN XY:

725534

show subpopulations

Gnomad4 AFR exome

AF:

0.0278

Gnomad4 AMR exome

AF:

0.0430

Gnomad4 ASJ exome

AF:

0.0939

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0972

Gnomad4 FIN exome

AF:

0.0873

Gnomad4 NFE exome

AF:

0.0777

Gnomad4 OTH exome

AF:

0.0675

GnomAD4 genome

AF:

0.0636

AC:

9673

AN:

152198

Hom.:

366

Cov.:

AF XY:

0.0628

AC XY:

4676

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0316

Gnomad4 AMR

AF:

0.0584

Gnomad4 ASJ

AF:

0.0985

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0891

Gnomad4 FIN

AF:

0.0915

Gnomad4 NFE

AF:

0.0812

Gnomad4 OTH

AF:

0.0711

Alfa

AF:

0.0761

Hom.:

634

Bravo

AF:

0.0576

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.0836

EpiControl

AF:

0.0769

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pyridoxal phosphate-responsive seizures

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Mar 02, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over